TCR Signaling in T Cell Memory

Abstract

T cell memory plays a critical role in our protection against pathogens and tumors. The antigen and its interaction with the T cell receptor (TCR) is one of the initiating elements that shape T cell memory together with inflammation and costimulation. Over the last decade, several transcription factors and signaling pathways that support memory programing have been identified. However, how TCR signals regulate them is still poorly understood. Recent studies have shown that the biochemical rules that govern T cell memory, strikingly, change depending on the TCR signal strength. Furthermore, TCR signal strength regulates the input of cytokine signaling, including pro-inflammatory cytokines. These highlight how tailoring antigenic signals can improve immune therapeutics. In this review, we focus on how TCR signaling regulates T cell memory and how the quantity and quality of TCR-peptide-MHC interactions impact the multiple fates a T cell can adopt in the memory pool.

Keywords: T cell; T cell receptor; immune memory; protective immunity; signaling.

Figure 1

Proposed model of how TCR signal strength regulates CD8 T cell memory differentiation. The interactions of TCR–pMHC on a naïve CD8 T cell triggers TCR signals of varying strength. A default TCR signal leads to low levels of T-bet and Blimp-1 and higher levels of Eomes and Bcl-6 skew the naïve T cell into a central-memory phenotype. This weak TCR signal can be achieved by strong or very weak ligands. If the TCR signal is intermediate, then T cells integrate IL-2 and other pro-inflammatory signals, which allow for similar up-regulation of all transcription factors depicted. This ensures the acquisition of effector function early in the response. Once antigen and inflammation decrease due to clearance of the pathogen, effector T cells decrease their levels of Blimp-1 and T-bet and regain higher ratios of Bcl-6/Blimp-1 and Eomes/T-bet allowing them to become memory T cells. For the cases where the naïve T cell receives very strong TCR signals, the Bcl-6/Blimp-1 and Eomes/T-bet ratios are too low and ultimately lead to apoptosis.